There is compelling evidence that the ability of odor detection has declined in Parkinson's disease (PD) patients indicating that odor detection could be used as a biomarker for Parkinson's disease. Immunohistochemical studies have shown that olfactory area has extremely high expression of metabotropic glutamate 5 receptors (mGluR5). Olfactory is an area, where recognition of odors is done. We have developed high level imaging instrumentation and techniques as well as unique ligands to conduct quantitative in vivo imaging studies of dopaminergic and glutamatergic neurofunction. Now, we propose to use this imaging battery with high level in vitro analysis of endpoint measures to investigate olfaction during progressive degeneration in a MPTP (1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of PD using two different odors; lemon and oregano. To investigate underlying mechanisms of olfaction and relation to PD-like progressive degeneration we will conduct longitudinal microPET imaging studies of dopaminergic function with [11C]CFT ([N-methyl-11C]-2-[unreadable]-carbomethoxy-3- [unreadable] -(4-fluorophenyl)tropane ) and mGluR5 function with [11C]M-PEPy (2-(2-(5-[11C]methoxypyridin-3-yl)ethynyl)pyridine). Parallel studies will be conducted in MPTP and control mice, correspondingly administered with saline. These studies will be completed with behavior analyses and end point immunohistochemical, Western Blot and enzymatic studies. With these studies we will investigate, 1) if olfactory bulb has progressive dopaminergic degeneration measured by microPET and [11C]CFT; 2) if odor induced response on mGluR5 function in olfactory bulb has correlation to dopaminergic degeneration measured in striatum during progressive degeneration; 3) if odor induced challenge on mGluR5 function has correlation to behavioral measures; 4) if odor sensitization depends on molecular structure or size of the odor molecule; and 5) if odor induced challenge on mGluR5 expression or carbo anhydrase VI or adenylyl cyclase measured from olfactory bulb, cilia or nasal mucus can be used as a biomarker for PD-like degeneration? Abstract There is compelling evidence that the ability of odor detection has declined in Parkinson's disease (PD) patients indicating that odor detection could be used as a biomarker for PD. To investigate olfaction and its relation to PD-like progressive degeneration we will conduct longitudinal in vivo imaging studies combined with in vitro analysis of endpoint measures in a MPTP mouse model of PD. [unreadable] [unreadable] [unreadable]